The antibody response to bacterial polysaccharide, lipopolysaccharide and protein antigens is critical to the development of protective immunity. Recent animal studies have indicated that a deficiency of vitamin A (retinol) significantly impairs the antibody response to certain bacterial antigens from organisms that are significant to human pathology. At the same time, several field studies conducted in developing countries have indicated that the mortality rate in young children, presumably from infectious diseases, is significantly reduced by periodic supplementation with vitamin A. The possibility that orally administered vitamin A has adjuvant-like activity in the immune response together with public health concerns about childhood vitamin A deficiency provide a strong impetus to understand the effects of both vitamin A deficiency and retinol supplementation on the immune system. In the past 4 years, we have developed a young rat model to study the effects of vitamin A deficiency and retinol supplementation on antibody production to bacterial antigens including pneumococcal polysaccharide, meningococcal polysaccharide and tetanus toxoid. This renewal proposal extends these observations, addressing nutritional and mechanistic questions of particular relevance to child health. In Aim 1 we will determine whether marginal vitamin A deficiency compromises the antibody response to pneumococcal polysaccharide or tetanus toxoid. In Aim 2, we will compare oral retinol with retinoic acid in terms of their abilities to restore the antibody response to each of these antigens. In Aim 3, we will evaluate the ability of oral retinol to stimulate antibody production to a conjugated polysaccharide vaccine, evaluating (a) the primary and secondary IgM and IgG responses, (b) the development of immunological memory, (c) the effects of oral vitamin A on IgG subclass selection and (d) any change in the ontogeny of antibody production. Aim 4 focuses on the adjuvant-like properties of orally administered retinol on the antibody response to tetanus toxoid, testing the hypothesis that macrophage-derived factors, including tumor necrosis factor-alpha and T cell-derived interferon-gamma are involved in adjuvanticity. In Aim 5, we will use the model of B cell activation by heterologous anti-IgD to examine the stages of B cell activation and T cell helper function at which vitamin A deficiency and retinol supplementation modulate the antibody response. We will correlate the immune response to measurements of tissue retinoid levels (Aim 6). Together, the proposed studies hold promise for understanding the potential for vitamin A to modulate the immune response, which is highly relevant to child health concerns in the United States and the developing world.